The crucial role of metal ions in neurodegeneration and the use of chelators as a promising therapeutic strategy have been reviewed by Gaeta and Hider (Gaeta, A. and Hider, R. C., British Journal of Pharmacology, 2005, 146, 1041-1059). In patients with Parkinson's disease (PD), the selective degeneration of the dopamine-containing region of the brain occurs. The iron levels in the substantia nigra (SN) are elevated. Fe(II) can react with hydrogen peroxide to generate hydroxyl radical, which in turn leads to cellular degeneration via the destruction of proteins, nucleic acids and phospholipids. It is proposed that reducing the free iron level with chelators can inhibit the onset of the disease, i.e., neural degeneration. The latter results in reducing dopaminergic cell loss. Examples of small molecule chelators for this utility are deferiprone, clioquinol, and desferrioxamine. These chelators have been claimed to reduce free iron levels in neural tissues as a means to reduce neural degeneration (US 2004/0101521). The reduction of iron-induced oxidative stress is protective to the neuron. Iron chelation appears to be one of the new approaches to combat neurodegenerative disease such as Alzheimer's disease (AD) and PD. An effective chelator can, in principle, prevent generation of hydroxyl radical induced by iron-hydrogen peroxide, and mobilize free chelatable iron from the brain, thus exerting its neuroprotective function.
Current drugs used for PD therapy include L-dopa, dopamine (DA) agonists, catechol O-methyl transferase inhibitors such as talcapone, and monoamine oxidase B (MAO-B) inhibitors such as rasagiline and selegiline. However, these drugs cannot mitigate the progression of the disease process. A research group from Israel reported the use of novel bifunctional iron chelators as potential agents in AD, PD and other neurodegenerative diseases (U.S. Pat. No. 6,855,711). The rationale is based on the observation that increased level of iron, and MAO-B activity in the brain are the major pathogenic factors in PD and other neurodegenerative diseases. Since iron chelators and MAO-B inhibitors have been shown to possess neuroprotective activity in animals, it is logical to connect the MAO-B inhibitor onto an iron chelator and apply such agents for the treatment and/or prevention of neurodegenerative diseases. One of the lead compounds is M30, an 8-hydroxyquinoline derivative (iron chelator) attached to a MAO-B inhibitor (Avramovich-Tirosh, Y., et al., Journal of Neurochemistry, 2007, 100, 490-502).
Amyloids are insoluble fibrous protein aggregations (usually polymeric). From a chemical perspective, amyloids form insoluble beta-pleated sheet structures and cannot be destroyed by proteases. Amyloid β (Aβ or Abeta) is a small peptide of 39-43 amino acids that is the main constituent of amyloid plaques in the brains of AD patients. AD is a dementia that results in the irreversible deterioration of mental function and eventually leads to the death of the patient. Aβ is also found in the brains of patients with Down's syndrome. Due to its more hydrophobic nature, the Aβ42 fragment is the most amyloidogenic form of the peptide allowing them to build up with other fragments to form AD plaque.
New therapeutic approaches to the treatment or prevention of AD involve slowing, or reversing Aβ accumulation. The mechanism of toxicity and the neurochemical events that cause Aβ deposition are still unclear, but transition metals such as copper, zinc (II) and iron (III) are found concentrated in and around amyloid plaques (Lovell, M. A., et al., J. Neurol. Sci. 1998, 158: 47-52). Aβ is known to exhibit a high affinity for transition metal ions. The binding of metal, in particular Zn++, and to a lesser extent Cu++ and Fe3+, to Aβ markedly increases its aggregation and the formation of amyloid deposits (Bush, A. I., et al., Science, 1994, 265: 1464-1467). Cherny et al. demonstrated that both processes (aggregation and deposition) can be reversed in the presence of metal-chelating agents (Cherny, R. A., et al., J. Biol. Chem. 1999, 274: 23223-23228). The binding of redox active transition metals (i.e., Cu2+ and Fe3+) to Aβ also leads to the generation of reactive oxygen species (Sayre, L. M., et al., J. Neurochem. 2000, 74: 270-279), which are known to have deleterious effects on a wide variety of biomolecules. Biometal- and amyloid-mediated production of reactive oxygen species are believed to be responsible, at least in part, for the oxidative stress observed in the brains of AD patients (Gabbita, S. P., et al., J. Neurochem. 1998, 71: 2034-2040).
Barnham et al. reported the use of chelators as metal-protein attenuating compounds (MPAC) for the treatment of AD (Barnham, K. J., et al., Drug Design Reviews—Online, 2004, 1, 75-82). The chelator is proposed to chelate the metal at the accumulation site in the brain and redistribute to other tissues inside the brain. The chelator clioquinol, 5-chloro-8-hydroxy-7-iodo-quinoline has been used as an oral drug in a phase II clinical trial (Ritchie, C. W., et al., Arch Neurol, 2003, 60, 1685-1691). Due to manufacturing problems with clioquinol and the presence of the 5,7-diiodo analogue, a replacement analogue to clioquinol is being developed by Prana Biotechnology Ltd. (Melbourne, Australia) for the treatment of AD.
The design and development of deferiprone, a low molecular weight iron chelator has been reviewed (Kontoghiorghes, G. J., et al., Current Medicinal Chemistry, 2004, 11 2161-83). In addition to its use in the treatment of the above neurogenerative diseases, deferiprone may also be used to redistribute iron in conditions such as Hallervorden-Spatz syndrome and Friedreich's ataxia.
The bidentate chelator deferiprone, 3-hydroxy-1,2-dimethyl-1H-pyridin-4-one is a drug used in the treatment of iron overload disease. The same drug can be used in non-iron overloaded conditions and towards the treatment of neurogenerative diseases (US 2004/0101521). In order to use a chelator to mobilize free chelatable iron from the brain and exert its neuroprotective function, the chelator must penetrate the blood brain barrier (BBB) to reach the neural tissues. Deferiprone is chosen because of its low molecular weight (139) and its ability to penetrate the BBB. For example, deferiprone has a distribution coefficient of 0.17 at pH 7.4 and its ability to penetrate the BBB can be estimated by an experimentally determined physico-chemical parameter kBMC wherein BMC is known as biopartitioning micellar chromatography. Escuder-Gilabert et al., reported the potential of BMC as an in vitro technique for predicting drug penetration across the BBB (Escuder-Gilabert, L., et al., Journal of Chromatrography B, 2004, 807, 193-201) and demonstrated the usefulness of BMC for correlating experimentally determined BBB penetration of drugs and determined the kBMC of more than 30 known central nervous system (CNS) drug substances.